Stable ophthalmic formulations

ABSTRACT

Disclosed herein are stable formulations suitable for the treatment of glaucoma and ocular hypertension.

RELATED APPLICATIONS

This application is a 35 U.S.C. 371 (national stage) application ofPCT/1B2008/003381 filed Nov. 7, 2008, which claims the benefit ofItalian Patent Application No. RM2008A000182 filed Apr. 7, 2008, and thebenefit of U.S. Provisional Patent Application No. 61/110,395 filed Oct.31, 2008, all of which are herein incorporated by reference in theirentirety.

FIELD OF THE APPLICATION

Described herein are composition and methods for treating ophthalmicconditions.

BACKGROUND OF THE INVENTION

Glaucoma is an ophthalmic disease that often manifests as a progressiveincrease in intraocular pressure. Untreated glaucoma leads to severedefects in the structure of the eye, particularly to damage of the headof the optic nerve, resulting in reduction of the visual field andoptical atrophy. In certain instances, the pathology is related toinsufficient drainage of aqueous humor from the eye. Other factors,including the production of aqueous humor and pressure on the episcleralveins, may also contribute to development of the condition.

SUMMARY OF THE INVENTION

Provided herein are stable ophthalmic formulations for the treatment ofophthalmic conditions, including conditions in which intraocularpressure (IOP) is greater than 21 mm Hg (“high IOP”). Such compositionsinclude, by way of example only, gel, ointments, solutions, viscoussolutions, eye drops, emulsions, gel-forming solutions and the like. Insome embodiments, the compositions are not in the form of suspensions.The stable ophthalmic formulations are used for the treatment ofglaucoma, ocular hypertension, or combinations thereof. Further, thestable ophthalmic formulations described herein are used for treatinghigh IOP resulting from traumatic hyphema, orbital edema, postoperativevisco-elastic retention, intraocular inflammation, corticosteroid use,pupillary block, or idiopathic causes. In some embodiments, the stableophthalmic formulations have at least one stability selected fromchemical stability, physical stability and physiological stability. Infurther embodiments, the stable ophthalmic formulations have at leasttwo of the aforementioned types of stability. In yet furtherembodiments, the stable ophthalmic formulations possess all three of theaforementioned types of stability.

In certain embodiments, the stable ophthalmic formulations have a pHbetween about 5.8 and 6.5, including a pH selected of about 5.8, about5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4 or about 6.5,and further, solubilized dorzolamide (or a pharmaceutically acceptablesalt thereof), including by way of example, dorzolamide complexed with atype of cyclodextrin. In one embodiment, the formulations are stableduring storage at temperatures of about 20° C. and above (including attemperatures of about 25° C. and above; at temperatures of about 28° C.and above; at temperatures of about 30° C. and above) for extendedperiods of time, and are well-tolerated when administered to the eye,even during long-term therapy. In certain embodiments, the cyclodextrinis hydroxypropyl-β-cyclodextrin (HP-β-cyclodextrin). Such stableophthalmic formulations include, by way of example only, gel, ointments,solutions, viscous solutions, eye drops, emulsions, gel-formingsolutions and the like. In some embodiments, the stable ophthalmicformulations are not in the form of suspensions.

In certain embodiments, the stable ophthalmic formulations comprise acombination of dorzolamide or a pharmaceutically acceptable salt thereofand latanoprost at therapeutically effective concentrations. In oneembodiment, the formulations are stable (i.e., chemically, physicallyand physiologically stable) during storage at temperatures 20° C. andabove (including at temperatures of about 25° C. and above; attemperatures of about 28° C. and above; at temperatures of about 30° C.and above) for extended periods of time, and are well-tolerated whenadministered to the eye, even during long-term therapy. The formulationsdisclosed herein comprise a stabilizing and solubilizing system thatsimplifies coadministration of the active agents. The stabilizing andsolubilizing system comprises a cyclodextrin and a pH in a range thatmaintains the integrity of the active agents and is well-tolerated bythe eye. In certain embodiments, the cyclodextrin ishydroxypropyl-β-cyclodextrin (HP-β-cyclodextrin). In some embodiments,the pH is between about 5.8 and 6.5, including a pH selected of about5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4 orabout 6.5. Such stable ophthalmic formulations include, by way ofexample only, gel, ointments, solutions, viscous solutions, eye drops,emulsions, gel-forming solutions and the like. In some embodiments, thestable ophthalmic formulations are not in the form of suspensions.

In some embodiments, a stable ophthalmic composition disclosed hereinfor the treatment of high IOP, including glaucoma, ocular hypertension,or a combination thereof comprises a cyclodextrin and a therapeuticallyeffective amount of a therapeutic component, wherein the composition hasa pH that is well-tolerated by the eye and maintains stability of thetherapeutic component, and wherein the therapeutic component comprisesdorzolamide or a pharmaceutically acceptable salt thereof andlatanoprost. In one embodiment, the formulations are stable duringstorage at temperatures 20° C. and above (including at temperatures ofabout 25° C. and above; at temperatures of about 28° C. and above; attemperatures of about 30° C. and above) for extended periods of time,and are well-tolerated when administered to the eye, even duringlong-term therapy. In some embodiments, after 6 months of storage at 25°C., a stable ophthalmic composition disclosed herein comprises at least97% of the initial amount of dorzolamide, and at least 98% of theinitial amount of latanoprost. In some embodiments, after 6 months ofstorage at 40° C., a stable ophthalmic composition disclosed hereincomprises at least 97% of the initial amount of dorzolamide, and atleast 98% of the initial amount of latanoprost. Such stable ophthalmiccomposition include, by way of example only, gel, ointments, solutions,viscous solutions, eye drops, emulsions, gel-forming solutions and thelike. In some embodiments, the stable ophthalmic compositions are not inthe form of suspensions.

In certain embodiments, an ophthalmic composition disclosed herein forthe treatment of high IOP, including glaucoma, ocular hypertension, or acombination thereof comprises a cyclodextrin and a therapeuticallyeffective amount of a therapeutic component, wherein the composition hasa pH between 5.8 and 6.5, and wherein the therapeutic componentcomprises dorzolamide or a pharmaceutically acceptable salt thereof andlatanoprost. In some embodiments, the pH is between about 5.8 and 6.5,including a pH selected of about 5.8, about 5.9, about 6.0, about 6.1,about 6.2, about 6.3, about 6.4 or about 6.5. In some embodiments, thepharmaceutically acceptable salt of dorzolamide is dorzolamidehydrochloride. In certain embodiments, the cyclodextrin isHP-β-cyclodextrin. In some specific embodiments, a composition disclosedherein comprises dorzolamide hydrochloride at 0.025-5 wt %, latanoprostat 0.001-5 wt %, and HP-β-cyclodextrin at 0.01-50 wt %. In certainembodiments, a composition disclosed herein comprises dorzolamidehydrochloride at 1-3 wt %, latanoprost at 0.003-0.01 wt %, andHP-β-cyclodextrin at 2-10 wt %.

In some embodiments, a composition disclosed herein further comprises atleast one agent selected from a mucoadhesive, a preservative, apH-adjusting agent, a tonicity-adjusting agent, a buffering agent, anantioxidant, a chelating agent, an antimicrobial preservative, achemical preservative, or a combination thereof. In some embodiments,the mucoadhesive is hyaluronic acid or a pharmaceutically acceptablesalt thereof (e.g., sodium hyaluronate), polyvinyl alcohol,polyvinyl-pyrrolidone, hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, a poloxamer, alginic acid, chitosan,xanthan gum, carrageenan, acrylic acid, acrylic acid derivatives, or acombination thereof. In some embodiments, the preservative isbenzalkonium chloride, chlorobutanol, phenylmercuric acetate,phenylmercuric nitrate, polyhexanide, cetrimide, cetylpyridiniumchloride, EDTA, or a combination thereof. In some embodiments, thepH-adjusting agent is hydrochloric acid, boric acid, acetic acid, sodiumhydroxide, potassium hydroxide, or a combination thereof. In someembodiments, the tonicity-adjusting agent is sodium chloride, potassiumchloride, mannitol, glycerol, sorbitol, xylitol, or a combinationthereof. In some embodiments, the buffering agent is boric acid, anacetate buffer, a citrate buffer, a phosphate buffer, a borate buffer,or a combination thereof. In some embodiments, the antioxidant is sodiummetabisulfite, sodium thiosulfate, acetyl cysteine, BHA, BHT, vitamin E,ascorbic acid, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid,or a combination thereof. Such composition include, by way of exampleonly, gel, ointments, solutions, viscous solutions, eye drops,emulsions, gel-forming solutions and the like. In some embodiments, thecompositions are not in the form of suspensions.

In some embodiments, a composition or formulation disclosed herein doesnot contain a buffer system. In further embodiments, a composition orformulation disclosed herein does not contain an antioxidant. In someembodiments, a composition disclosed herein contains neither a buffersystem nor an antioxidant. In some embodiments, a composition orformulation disclosed herein does not contain a antimicrobialpreservative.

In some embodiments, a composition disclosed herein further comprises atherapeutically effective amount of an additional anti-glaucoma agent.In certain embodiments, the additional anti-glaucoma agent is a betablocker. In certain specific embodiments, the beta blocker is timolol.

Further disclosed herein is a method of treating high IOP, includingglaucoma, ocular hypertension, or a combination thereof comprisingtopically administering a composition disclosed herein to the eye of apatient in need thereof.

Also disclosed herein is a method of stabilizing an ophthalmiccomposition comprising dorzolamide or a pharmaceutically acceptable saltthereof and latanoprost, said method comprising incorporating acyclodextrin into the formulation and adjusting the pH to a range thatis well-tolerated by the eye and maintains stability of each of theactive agents. In some embodiments, after 6 months of storage at 25° C.,the composition stabilized by the method comprises at least 97% of theinitial amount of dorzolamide, and at least 98% of the initial amount oflatanoprost. In some embodiments, after 6 months of storage at 40° C.,the composition stabilized by the method comprises at least 97% of theinitial amount of dorzolamide, and at least 98% of the initial amount oflatanoprost. In some embodiments, the cyclodextrin used in the method ofstabilizing a composition comprising dorzolamide or a pharmaceuticallyacceptable salt thereof and latanoprost is HP-β-cyclodextrin.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are compositions comprising at least two differentactive agents. In other words, provided herein are compositionscomprising a first active agent and a second active agent. In specificembodiments, the first active agent is a carbonic anhydrase inhibitor(e.g., dorzolamide or a pharmaceutically acceptable salt thereof, suchas dorzolamide hydrochloride). In specific embodiments, the secondactive agent is a hypotensive agent (e.g., an ophthalmic hypotensiveagent). In more specific embodiments, the hypotensive agent is aprostaglandin (e.g., a PGF_(2α) prostaglandin such as latanoprost). Infurther embodiments, compositions described herein optionally compriseone or more additional active agents (e.g., a third active agent, afourth active agent, and the like). In some embodiments, thecompositions described herein are pharmaceutical compositions. Incertain embodiments, the pharmaceutical compositions described hereinare formulated for topical administration. In further or alternativeembodiments, the compositions described herein are formulated forophthalmic administration (e.g., as a collyrium). In certainembodiments, ophthalmic compositions and formulations described hereinare well-tolerated by the eye. In some embodiments, ophthalmicformulations described herein are useful for the treatment of high IOP,including glaucoma, ocular hypertension, or a combination thereof. Suchophthalmic formulations include, by way of example only, gel, ointments,solutions, viscous solutions, eye drops, emulsions, gel-formingsolutions and the like. In some embodiments, the ophthalmic formulationsare not in the form of suspensions.

In certain instances, compositions and formulations described hereincomprise a first active agent suitable for the treatment of high IOPincluding glaucoma, ocular hypertension, or a combination thereof and asecond active agent suitable for the treatment of high IOP includingglaucoma, ocular hypertension, or a combination thereof. In certaininstances, compositions and formulations described here simplifycoadministration of the at least two different active agents for thetreatment of high IOP including glaucoma, ocular hypertension, or acombination thereof. In some instances, coadministration of the at leasttwo different active agents in a single formulation results in anadditive or synergistic treatment efficacy relative to administration ofthe agents individually and/or separately. In some instances,coadministration of the active agents in a single formulation reducesthe possibility of dosing errors or missed treatments that result fromadministration of the compounds in separate formulations. Thus, incertain instances, coadministration of the active agents in aformulation disclosed herein results in overall better patientcompliance for the treatment of high IOP including glaucoma, ocularhypertension, or a combination thereof with the at least two differentactives.

In certain embodiments, a composition or formulation described hereincomprises a first active agent and/or the second active agent, both ofwhich are solubilized in a liquid medium (aqueous medium). In someembodiments, at least one of the solubilized active agents is complexedwith a complexing agent and the combination thereof is dissolved. Insome embodiments, the active agent is dissolved without being complexedby a complexing agent. In some embodiments, the complexing agent is acyclodextrin. In some embodiments, at least one active agent forms aninclusion complex with the cyclodextrin.

In some embodiments, compositions and formulations described hereincomprise a first active agent and a second active agent, wherein thefirst active agent and the second active agent are formulated into thecomposition or formulation in a manner that allows ophthalmic and/ortopical activity of the agents (e.g., by formulating a composition orformulation described herein as a solution, gel, or the like, comprisinga first active agent and a second active agent as solutes within thesolution, gel, etc.). It is to be understood that such compositions andformulations include compositions and formulations wherein a substantialportion, a therapeutically effective portion, most or all of the firstand second agents are dissolved in the liquid medium (e.g., aqueousmedium).

In some embodiments, compositions and formulations described hereincomprise a stabilizing agent. In certain embodiments, the stabilizingagent enhances the chemical stability (e.g., inhibition of degradationof one or more of the active agents present), physiological stability(i.e., post-administration degradation) and/or physical stability (e.g.,substantially maintaining the concentration of one or more of the activeagents dissolved in the liquid medium) of the composition orformulation. In specific embodiments, stabilizing agents useful hereininclude, by way of non-limiting example, one or more cyclodextrin (e.g.,hydroxypropyl-β-cyclodextrin).

In specific embodiments, provided herein are stable compositions andformulations comprising a carbonic anhydrase inhibitor (e.g.,dorzolamide or a pharmaceutically acceptable salt thereof, such asdorzolamide hydrochloride), and a hypotensive agent (e.g., aprostaglandin, including, by way of non-limiting example, a PGF_(2α)prostaglandin such as latanoprost). In more specific embodiments,provided herein are stable compositions and formulations comprising acarbonic anhydrase inhibitor (e.g., dorzolamide or a pharmaceuticallyacceptable salt thereof, such as dorzolamide hydrochloride), ahypotensive agent (e.g., a prostaglandin, including, by way ofnon-limiting example, a PGF_(2α) prostaglandin such as latanoprost), andan aqueous medium. In still more specific embodiments, provided hereinare stable compositions and formulations comprising a carbonic anhydraseinhibitor (e.g., dorzolamide or a pharmaceutically acceptable saltthereof, such as dorzolamide hydrochloride), a hypotensive agent (e.g.,a prostaglandin, including, by way of non-limiting example, a PGF_(2α)prostaglandin such as latanoprost), an aqueous medium, and a stabilizingagent (e.g., a cyclodextrin, such as hydroxypropyl-β-cyclodextrin). Incertain embodiments, such compositions are well-tolerated by the eye.

In some embodiments, any of the compositions or formulations describedherein are stable compositions or formulations. Included within theconcept of stable compositions or formulations are the chemicalstability, physiological, and/or physical stability of the compositionor formulation. In some embodiments, the stability is provided by use ofa stabilizer and/or by adjusting the pH to between about 5.8 and about6.5. In some embodiments, the stabilizer is a cyclodextrin. In someembodiments, the stabilizer provides one form of stability to one activeingredient (e.g., physical stability) and another form of stability to asecond active ingredient (e.g., chemical stability).

In certain instances, chemical stability refers to the inhibition ofdegradation of one or more of the active agents present. In someembodiments, chemical stability of a composition or formulationdescribed herein includes the chemical stability of at least one activeagent, the first active agent, the second active agent, or all activeagents present in the composition or formulation. In certain instances,chemical stability refers to the stability of a composition,formulation, or agent against degradation. Thus, in some instances, thechemical stability of an agent is determined by measuring the amount ofthe agent that is present at an initial time (e.g., at the time offormulation) and a second later time; and determining the amount orpercent decrease in the agent over the time between the initial time andthe second later time.

In some instances, physical stability refers to substantiallymaintaining constitution of the formulation or composition. In certainembodiments wherein a composition or formulation described hereincomprises at least two different active agents and a liquid medium(e.g., an aqueous medium), physical stability refers to the maintenanceof a substantially similar amount and/or therapeutically effectiveamount of the active agents dissolved in the liquid medium. Thus, incertain instances, agents that enhance the physical stability of acomposition or formulation described herein include solubilizers.

In some instance, physiological stability refers to substantiallymaintaining the therapeutic activity of the dorzolamide and/orlatanoprost after administration of the ophthalmic formulation to theeye. That is, stabilization to physiological degradation of the activeagents.

In some embodiments, the stable compositions or formulations areformulated with a pH between about 5.8 and 6.5, including a pH selectedof about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3,about 6.4 or about 6.5. In certain embodiments, stability includeschemical, physiological, and/or physical stability. In certainembodiments, the compositions or formulations are stable during storageat temperatures 20° C. and above for extended periods of time, and arewell-tolerated when administered to the eye, even during long-termtherapy.

In certain embodiments, provided herein are methods of treating glaucomain an individual comprising administering to an individual in needthereof an effective amount of any composition or formulation describedherein. In some embodiments, provided herein are methods of treatingocular hypertension in an individual comprising administering to anindividual in need thereof an effective amount of any composition orformulation described herein.

Actives

In certain embodiments, the compositions and formulations describedherein comprise at least two different active agents. In someembodiments, the at least two active agents comprise at least two activeagents that are suitable for the treatment of high IOP includingglaucoma, ocular hypertension, or a combination thereof. In certainembodiments, the at least two active agents comprise at least two activeagents selected from the group consisting of a carbonic anhydraseinhibitor, a prostaglandin, and a beta blocker.

In some embodiments, the compositions and formulations described hereincomprise at least two different active agents (i.e., a first activeagent and a second active agent). In some instances, the at least twodifferent active agents are both active agents suitable for thetreatment of high IOP including glaucoma, ocular hypertension, or acombination thereof. In some embodiments, the first active agent (i.e.,one of the at least two different active agents) is a carbonic anhydraseinhibitor. In certain embodiments, the carbonic anhydrase inhibitor isdorzolamide or a pharmaceutically acceptable salt thereof. In specificembodiments, the pharmaceutically acceptable salt of dorzolamide isdorzolamide hydrochloride.

In certain embodiments, the carbonic anhydrase inhibitor (e.g.,dorzalamide or dorzolamide hydrogen chloride) is present in acomposition or formulation described herein in an amount of about0.025-5 wt %, or about 1-3 wt %, about 2 wt %, or about 2.2 wt %.

In certain embodiments, the second active agent (i.e., one of the atleast two different active agents) is a hypotensive agent (e.g., anophthalmic hypotensive agent). In some embodiments, the hypotensiveagent is a prostaglandin. In some embodiments, the prostaglandin is aPGF_(2α) prostaglandin. In some embodiments, the PGF_(2α) prostaglandinis latanoprost.

In some embodiments, the hypotensive agent (e.g., a prostaglandin, suchas a PGF_(2α) prostaglandin such as latanoprost) is present in acomposition or formulation described herein in an amount of about0.001-5 wt %, about 0.003-0.01 wt %, or about 0.005 wt %.

In some embodiments, the at least two different active agents for thetreatment of glaucoma comprise a beta blocker.

In certain embodiments, a composition or formulation described hereinfurther comprises a third active agent. In some embodiments, the thirdactive agent is a beta blocker. In certain embodiments, the beta blockeris timolol or a pharmaceutically acceptable salt thereof. In someembodiments, the pharmaceutically acceptable salt of timolol is timololmaleate.

In some instances, the at least two different active agents for thetreatment of high IOP including glaucoma, ocular hypertension, or acombination thereof comprise a carbonic anhydrase inhibitor and aprostaglandin. In certain embodiments, the at least two different activeagents for the treatment of high IOP including glaucoma, ocularhypertension, or a combination thereof comprise dorzolamide or apharmaceutically acceptable salt thereof as the carbonic anhydraseinhibitor and latanoprost as the prostaglandin. Dorzolamide andlatanoprost are useful for the treatment of intraocular hypertension andantiglaucoma topical therapy; the increase in uveoscleral flow and thereduction in the production of aqueous humor are complementarymechanisms reduced respectively by each of these agents.

In some instances, the at least two different active agents for thetreatment of high IOP including glaucoma, ocular hypertension, or acombination thereof comprise a carbonic anhydrase inhibitor, aprostaglandin, and a beta blocker. In certain embodiments, the at leasttwo different active agents for the treatment of high IOP includingglaucoma, ocular hypertension, or a combination thereof comprisedorzolamide or a pharmaceutically acceptable salt thereof, latanoprost,and timolol.

In certain embodiments, actives described herein are present in acomposition or formulation described herein in a therapeuticallyeffective amount. It is to be understood that in some instances, atherapeutically effective amount of an active when combined with adifferent active is less than a therapeutically effective amount of theactive if administered separately or individually.

Stability

In certain embodiments, the formulations disclosed herein providechemical stability of the at least two active agents. In other words, incertain embodiments, compositions and formulations disclosed hereinmaintain the stability of the at least two active agents and/or inhibitdegradation of the at least two active agents contained therein. Incertain instances, chemically stable compositions and formulationsprovided herein comprise a first active agent that is chemically stablein the composition or formulation and a second active agent that ischemically stable in the composition or formulation. In some instances,chemically stable includes thermal stability. Thus, in some embodiments,compositions, formulations and active agents (e.g., as formulated)described herein are thermally stable. In certain embodiments,compositions, formulations and active agents (e.g., as formulated)described herein are thermally stable at reduced temperature, at roomtemperature, at ambient temperatures, at about 25° C., at elevatedtemperatures, at about 40° C., or the like.

In some embodiments, the compositions and formulations disclosed hereinare physical stable. In certain embodiments, physical stability includesthe maintenance of a suitable physical form of one or both of the atleast two active agents within a composition or formulation describedherein. In certain embodiments, physically stable ophthalmic and/ortopically active formulations comprising a first active agent, a secondactive agent and a liquid medium (e.g., aqueous medium) describedherein, substantially retain their ophthalmic and/or topical activityafter storage. In some instances, such compositions substantially retaintheir ophthalmic and/or topical active after storage as determined bywhether or not the first and/or second active agents substantiallyretain the level of dissolution in a liquid medium as initiallyformulated or measured. In certain embodiments, physically stableophthalmic and/or topically active formulations comprising a firstactive agent, a second active agent and a liquid medium (e.g., aqueousmedium) described herein, substantially retain the level of dissolutionin a liquid medium as initially formulated or measured. In someinstances, determination of the level of physical stability of acomposition and/or the level of dissolution of agents within acomposition or formulation described herein can be determined bymeasuring the osmolarity of the composition over a period of time.

Latanoprost has scarce stability due to degradation when formulated inan isotonic solution comprising chloride benzalkonium (as apreservative) and buffered at a pH of 6.8. Such formulations must bepacked in plastic containers of 2.5 mL and stored at a temperature ofbetween 2° C. and 8° C. in order to avoid degradation. Latanoprostslowly degrades at temperatures of 4° C. and 25° C. with linearprogression, but degrades with polynomial progression of the secondorder at temperatures of 50° C. and 75° C. Although the rate ofdegradation at temperatures between 4° C. and 25° C. is not significant,at higher temperatures the rate of degradation increases substantially.For example, at temperatures of 50° C. and 75° C., the time taken by theconcentration of latanoprost to drop to 90% of an initial content is 198and 32 hours, respectively. As a result, prior art latanoprostformulations were refrigerated for storage, and prior art latanoprostformulations were not stored at temperatures above about 20° C. andabove (including at temperatures of about 25° C. and above; attemperatures of about 28° C. and above; at temperatures of about 30° C.and above) for extended periods of time.

Provided herein are stable compositions and formulations comprising aprostaglandin (e.g., latanoprost), wherein the prostaglandin (e.g.,latanoprost) is stable in the composition (e.g., upon storage). Inspecific embodiments, the prostaglandin (e.g., latanoprost) is thermallystable in the composition or formulation (e.g., upon storage). In someembodiments, the prostaglandin (e.g., latanoprost) is formulated with astabilizing agent (e.g., a cyclodextrin, such ashydroxypropyl-β-cyclodextrin). In more specific embodiments, the amountof latanoprost in a composition or formulation described herein afterstorage at 25° C. for 6 months is about 97% or more, about 98% or more,about 99% or more of an initial amount of latanoprost in the compositionor formulation. In certain instances, the initial amount of latanoprostin the composition or formulation refers to the amount of latanoprost inthe composition or formulation at any time (t₀) that the amount oflatanoprost is measured and later compared against (e.g., when thecomposition or formulation is first prepared or one month after thecomposition or formulation is first prepared). In some embodiments, theamount of latanoprost in a composition or formulation described hereinafter storage at 25° C. for 5 months is about 97% or more, about 98% ormore, about 99% or more of an initial amount of latanoprost in thecomposition or formulation. In certain embodiments, the amount oflatanoprost in a composition or formulation described herein afterstorage at 25° C. for 4 months is about 99% or more of an initial amountof latanoprost in the composition or formulation. In some embodiments,the amount of latanoprost in a composition or formulation describedherein after storage at 40° C. for 6 months is about 97% or more, about98% or more, about 99% or more of an initial amount of latanoprost inthe composition or formulation. In certain embodiments, the amount oflatanoprost in a composition or formulation described herein afterstorage at 40° C. for 5 months is about 99% or more of an initial amountof latanoprost in the composition or formulation. In specificembodiments, the pH of a formulation having such a stability has a pHbetween about 5.8 and 6.5, including a pH selected of about 5.8, about5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4 or about 6.5.In further or alternative embodiments, the composition further comprisesa carbonic anhydrase inhibitor (e.g., dorzolamide or dorzolamidehydrogen chloride) and a cyclodextrin (e.g.,hydroxypropyl-β-cyclodextrin). In more specific embodiments, thecomposition or composition comprises a carbonic anhydrase inhibitor(e.g., dorzolamide or dorzolamide hydrogen chloride), a prostaglandin(e.g., a PGF_(2α) prostaglandin such as latanoprost), a stabilizer(e.g., a cyclodextrin, such as hydroxypropyl-β-cyclodextrin), and aliquid medium (e.g., an aqueous medium).

Provided herein are compositions and formulations comprising a carbonicanhydrase inhibitor (e.g., dorzolamide or dorzolamide hydrogenchloride), wherein the carbonic anhydrase inhibitor (e.g., dorzolamideor dorzolamide hydrogen chloride) is stable in the composition (e.g.,upon storage). In specific embodiments, the carbonic anhydrase inhibitor(e.g., dorzolamide or dorzolamide hydrogen chloride) is thermally stablein the composition or formulation (e.g., upon storage). In more specificembodiments, the amount of dorzolamide or dorzolamide hydrogen chloridein a composition or formulation described herein after storage at 25° C.for 6 months is about 93% or more, about 94% or more, about 95% or more,about 96% or more, about 97% or more, about 98% or more, about 99% ormore of an initial amount of dorzolamide or dorzolamide hydrogenchloride in the composition or formulation. In certain instances, theinitial amount of dorzolamide or dorzolamide hydrogen chloride in thecomposition or formulation refers to the amount of dorzolamide ordorzolamide hydrogen chloride in the composition or formulation at anytime (t₀) that the amount of dorzolamide or dorzolamide hydrogenchloride is measured and later compared against (e.g., when thecomposition or formulation is first prepared or one month after thecomposition or formulation is first prepared). In some embodiments, theamount of dorzolamide or dorzolamide hydrogen chloride in a compositionor formulation described herein after storage at 25° C. for 5 months isabout 94% or more, about 95% or more, about 96% or more, about 97% ormore, about 98% or more, about 99% or more of an initial amount ofdorzolamide or dorzolamide hydrogen chloride in the composition orformulation. In certain embodiments, the amount of dorzolamide ordorzolamide hydrogen chloride in a composition or formulation describedherein after storage at 25° C. for 4 months is about 95% or more, about96% or more, about 97% or more, about 98% or more, about 99% or more ofan initial amount of dorzolamide or dorzolamide hydrogen chloride in thecomposition or formulation. In some embodiments, the amount ofdorzolamide or dorzolamide hydrogen chloride in a composition orformulation described herein after storage at 25° C. for 3 months isabout 97% or more, about 98% or more, about 99% or more of an initialamount of dorzolamide or dorzolamide hydrogen chloride in thecomposition or formulation. In certain embodiments, the amount ofdorzolamide or dorzolamide hydrogen chloride in a composition orformulation described herein after storage at 25° C. for 2 months isabout 99% or more of an initial amount of dorzolamide or dorzolamidehydrogen chloride in the composition or formulation. In someembodiments, the amount of dorzolamide or dorzolamide hydrogen chloridein a composition or formulation described herein after storage at 40° C.for 6 months is about 90% or more, about 91% or more, about 92% or more,about 93% or more, about 94% or more, about 95% or more, about 96% ormore, about 97% or more, about 98% or more, about 99% or more of aninitial amount of dorzolamide or dorzolamide hydrogen chloride in thecomposition or formulation. In certain embodiments, the amount ofdorzolamide or dorzolamide in a composition or formulation describedherein after storage at 40° C. for 5 months is about 94% or more, about95% or more, about 96% or more, about 97% or more, about 98% or more,about 99% or more of an initial amount of dorzolamide or dorzolamide inthe composition or formulation. In some embodiments, the amount ofdorzolamide or dorzolamide hydrogen chloride in a composition orformulation described herein after storage at 40° C. for 4 months isabout 91% or more, about 92% or more, about 93% or more, about 94% ormore, about 95% or more, about 96% or more, about 97% or more, about 98%or more, about 99% or more of an initial amount of dorzolamide ordorzolamide hydrogen chloride in the composition or formulation. Incertain embodiments, the amount of dorzolamide or dorzolamide in acomposition or formulation described herein after storage at 40° C. for3 months is about 93% or more, about 94% or more, about 95% or more,about 96% or more, about 97% or more, about 98% or more, about 99% ormore of an initial amount of dorzolamide or dorzolamide in thecomposition or formulation. In some embodiments, the amount ofdorzolamide or dorzolamide hydrogen chloride in a composition orformulation described herein after storage at 40° C. for 2 months isabout 96% or more, about 97% or more, about 98% or more, about 99% ormore of an initial amount of dorzolamide or dorzolamide hydrogenchloride in the composition or formulation. In certain embodiments, theamount of dorzolamide or dorzolamide in a composition or formulationdescribed herein after storage at 40° C. for 1 months is about 99% ormore of an initial amount of dorzolamide or dorzolamide in thecomposition or formulation. In specific embodiments, the pH of aformulation having such a stability has a pH between about 5.8 and 6.5,including a pH selected of about 5.8, about 5.9, about 6.0, about 6.1,about 6.2, about 6.3, about 6.4 or about 6.5. In further or alternativeembodiments, the composition further comprises a prostaglandin (e.g., aPGF_(2α) prostaglandin such as latanoprost) and a cyclodextrin (e.g.,hydroxypropyl-β-cyclodextrin). In more specific embodiments, thecomposition or composition comprises a carbonic anhydrase inhibitor(e.g., dorzolamide or dorzolamide hydrogen chloride), a prostaglandin(e.g., a PGF_(2α) prostaglandin such as latanoprost), a stabilizer(e.g., a cyclodextrin, such as hydroxypropyl-β-cyclodextrin), and aliquid medium (e.g., an aqueous medium).

Provided herein are compositions and formulations comprising a carbonicanhydrase inhibitor (e.g., dorzolamide or dorzolamide hydrogenchloride), a prostaglandin (e.g., a PGF_(2α) prostaglandin such aslatanoprost), a stabilizer (e.g., a cyclodextrin, such ashydroxypropyl-β-cyclodextrin), and a liquid medium (e.g., an aqueousmedium). In certain embodiments, such compositions and formulations arephysically stable. In some instances, physical stability is determinedas an ability of composition or formulation to maintain a certainosmolarity. In some embodiments, physically stable compositions andformulations described herein substantially maintain an osmolarity(e.g., a variation of less than about 2% over a period of about 5 monthsat 25° C.). In certain embodiments, physically stable compositions andformulations described herein comprise and substantially maintain anosmolarity and/or pH that is physiologically acceptable. In specificinstances, a physiologically acceptable osmolarity is about 280 mOsm/Lto about 320 mOsm/L. In some embodiments, compositions and formulationsdescribed herein are substantially stable (physical and/or chemical)under physiologically acceptable osmolarities and/or physiologicallyacceptable pH values.

In some embodiments, formulations disclosed herein provide suitablestability to a prostaglandin (e.g., a PGF_(2α) prostaglandin such aslatanoprost). In certain embodiments, the stability of latanoprost ismaintained in the presence of a stabilizer (e.g., a cyclodextrin, suchas hydroxypropyl-β-cyclodextrin) at a pH lower than 6.7-6.8.Surprisingly, in some embodiments, the stability of a prostaglandin(e.g., a PGF_(2α) prostaglandin such as latanoprost) in the presence ofa stabilizer (e.g., a cyclodextrin, such ashydroxypropyl-β-cyclodextrin) and a carbonic anhydrase inhibitor (e.g.,dorzolamide or dorzolamide hydrogen chloride) is maintained at a pHbetween about 5.8 and 6.5, including a pH selected of about 5.8, about5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4 or about 6.5.Thus, in specific embodiments, compositions and formulations describedherein have a pH of about 5.8 to about 6.5. Thus, in specificembodiments, compositions and formulations described herein have a pH ofabout 5.8 to about 6.4. Thus, in specific embodiments, compositions andformulations described herein have a pH of about 5.8 to about 6.3. Thus,in specific embodiments, compositions and formulations described hereinhave a pH between about 5.8 and 6.5, including a pH selected of about5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4 orabout 6.5.

Provided herein are compositions and formulations comprising a carbonicanhydrase inhibitor (e.g., dorzolamide or dorzolamide hydrogenchloride), a prostaglandin (e.g., a PGF_(2α) prostaglandin such aslatanoprost), a stabilizer (e.g., a cyclodextrin, such ashydroxypropyl-β-cyclodextrin), and a liquid medium (e.g., an aqueousmedium), wherein the composition or formulation has a pH between about5.8 and 6.5, including a pH selected of about 5.8, about 5.9, about 6.0,about 6.1, about 6.2, about 6.3, about 6.4 or about 6.5.

Tolerability

In further or alternative embodiments, formulations disclosed hereincomprise a pH that is well-tolerated by the eye. In some embodiments, apH that is well-tolerated by the eye does not cause symptoms of eyeirritation when the formulations are administered to the eye. In certainembodiments, symptoms of eye irritation include conjunctival burningand/or redness of the ocular surface. In some embodiments, by having apH that is well-tolerated by the eye, formulations disclosed hereinimprove patient compliance with a treatment regimen comprisingadministration of at least two different active agents for the treatmentof high IOP including glaucoma, ocular hypertension, or a combinationthereof.

Pharmaceutical compositions comprising dorzolamide hydrochloride (e.g.,2.2% by weight, 2% by weight of the free base) have a maximum solubilityat a pH of 5.6 (about 50 mg/mL). Because of structural characteristicsof dorzolamide hydrochloride, it is not very soluble at neutral pHlevels. Indeed, the solubility of dorzolamide hydrochloride decreasessignificantly at pH values in excess of 5.6 and, absent the use of othersolubilizing techniques, ophthalmic compositions comprising dorzolamidehydrochloride are not typically used at a pH of greater than 5.65. Suchcompositions are poorly tolerated by the eye, however, causing burningand/or redness of the ocular surface and having reduced levels ofpatient compliance. Furthermore, formulations of dorzolamidehydrochloride are often dosed multiple times a day (e.g., 3 times perday), and the stinging/burning of the formulation becomes quitenoticeable and unpleasant to the patient.

In certain instances, pH values that are well-tolerated by the eye aregreater than 5.65. In some instances, pH values that are well-toleratedby the eye have decreased incidences of burning and/or redness of theocular surface compared the burning and/or redness of the ocular surfacecaused by administration of a composition or formulation having a pH of5.65 or less. In some instances, pH values that are well-tolerated bythe eye are pH values that do not cause burning and/or redness of theocular surface when administered to the eye. In certain instances,compositions and formulations with pH values that are well-tolerated bythe eye have increased levels of patient compliance (and therebyincreased efficacy) compared to less-tolerated compositions (e.g.,compositions with pH values of 5.65 or less).

A series of experiments, discussed further below, unexpectedly indicatethat dorzolamide or a pharmaceutically acceptable salt thereof can beformulated with latanoprost at a pH that is not considered appropriatefor solubilizing dorzolamide (e.g., above 5.65) or for the formulationof latanoprost (e.g., 6.7-6.8). Furthermore, the pH range that providesappropriate solubility and stability of dorzolamide and latanoprost isalso well-tolerated by the eye when used in topical treatment of highIOP including glaucoma, ocular hypertension, or a combination thereof.By virtue of being well-tolerated by the eye, the formulations disclosedherein further improve patient compliance with a treatment regimencomprising both of the actives. This is particularly true with respectto dorzolamide, which is administered at pH levels below 5.65, causing aseries of side effects including conjunctival burning and redness of theocular surface.

Stabilizers

In some embodiments, compositions and formulations described hereincomprise a stabilizing agent. In certain embodiments, the stabilizingagent enhances the chemical stability, physiological, and/or physicalstability of the composition or formulation. In specific embodiments,stabilizing agents useful herein include, by way of non-limitingexample, one or more cyclodextrin (e.g., hydroxypropyl-β-cyclodextrin).

In some embodiments, the formulations disclosed herein comprise acyclodextrin. In certain embodiments, the cyclodextrin isHP-β-cyclodextrin. Other possible stabilizing agents include, by way ofnon-limiting example, lipid emulsions of polyvinilic alcohol.

In certain embodiments, the amount of stabilizer (e.g., a cyclodextrin,such as hydroxypropyl-β-cyclodextrin) present is about 1% or more toabout 8% or more, going respectively from a pH of 6.0 to a pH of 6.8(e.g., when the hydroxypropyl-β-cyclodextrin is characterized by anaverage degree of substitution of 6.1 (determined by NMR) and an averagemolecular weight of 1630 g/mol). Other hydroxypropyl-β-cyclodextrins(e.g., characterized by a different degree of substitution) are alsosuitably used in the formulations described herein, and in certainembodiments, are utilized by adjusting the concentration of thecyclodextrin to obtain similar results.

In some embodiments, a composition or formulation described hereincomprises about 2 wt % to about 10 wt % of a stabilizer (e.g., acyclodextrin such as HP-β-cyclodextrin).

Formulations

In certain embodiments, compositions and formulations described hereincomprise a carbonic anhydrase inhibitor (e.g., dorzolamide or apharmaceutically acceptable salt thereof, such as dorzolamidehydrochloride), a hypotensive agent (e.g., an a PGF_(2α) prostaglandinsuch as latanoprost), and a stabilizer (e.g., a cyclodextrin, such ashydroxypropyl-β-cyclodextrin). In some embodiments, the carbonicanhydrase inhibitor (e.g., dorzolamide or a pharmaceutically acceptablesalt thereof, such as dorzolamide hydrochloride) and a hypotensive agent(e.g., an a PGF_(2α) prostaglandin such as latanoprost) are present in atherapeutically acceptable amount.

In certain embodiments, formulations (e.g., aqueous formulations)prepared according to the instant disclosure comprise components in theweight percentages set forth below (Table 1), and have a pH betweenabout 5.8 and 6.5, including a pH selected of about 5.8, about 5.9,about 6.0, about 6.1, about 6.2, about 6.3, about 6.4 or about 6.5.

TABLE 1 Component Amount Dorzolamide hydrochloride 0.025-5.0%Latanoprost 0.001-5.0% HP-β-cyclodextrin  0.010-50.0%

According to certain specific embodiments, compositions disclosed hereincomprise the components in the weight proportions set forth in Table 2,and have a pH between about 5.8 and 6.5, including a pH selected ofabout 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about6.4 or about 6.5.

TABLE 2 Component Amount Dorzolamide hydrochloride 1.0-3.0% Latanoprost0.003-0.010% HP-β-cyclodextrin 2.00-10.0%

Formulations disclosed herein optionally further comprise additionalanti-glaucoma agents. In some embodiments, an additional anti-glaucomaagent is a beta blocker. In certain embodiments, the beta blocker istimolol or a pharmaceutically acceptable salt thereof. In certainspecific embodiments, timolol is present as its maleate salt at 0.1% byweight.

Formulations disclosed herein optionally further comprise hyaluronicacid or a pharmaceutically acceptable salt thereof, e.g., sodiumhyaluronate. In addition to its recognized functions, including as amucoadhesive agent, the presence of hyaluronate in the compositionincreases the ocular bioavailability of dorzolamide. In someembodiments, sodium hyaluronate is present in the formulations at0.01-0.10 wt %. In certain specific embodiments, sodium hyaluronate ispresent in the formulations at about 0.05 wt %.

Formulations disclosed herein also optionally further comprise one ormore ophthalmic excipient. Ophthalmic excipients include, by way ofnon-limiting example, at least one agent selected from a mucoadhesive, apreservative, a pH-adjusting agent, a tonicity-adjusting agent, abuffering agent, an antioxidant, a chelating agent, an antimicrobialpreservative, a chemical preservative, or a combination thereof. In someembodiments, the mucoadhesive is hyaluronic acid or a pharmaceuticallyacceptable salt thereof (e.g., sodium hyaluronate), polyvinyl alcohol,polyvinyl-pyrrolidone, hydroxypropyl-methylcellulose,carboxymethyl-cellulose, hydroxyethyl cellulose, a poloxamer, alginicacid, chitosan, xanthan gum, carrageenan, acrylic acid, acrylic acidderivatives, or a combination thereof. In some embodiments,mucoadhesives are present in the formulation at 0.01-10 wt %. In someembodiments, the preservative is benzalkonium chloride, chlorobutanol,phenylmercuric acetate, phenylmercuric nitrate, polyhexanide, cetrimide,cetylpyridinium chloride, EDTA, or a combination thereof. In someembodiments, the pH-adjusting agent is hydrochloric acid, boric acid,acetic acid, sodium hydroxide, potassium hydroxide, or a combinationthereof. In some embodiments, the tonicity-adjusting agent is sodiumchloride, potassium chloride, mannitol, glycerol, sorbitol, xylitol, ora combination thereof. In some embodiments, the buffering agent is anacetate buffer, a citrate buffer, a phosphate buffer, a borate buffer,or a combination thereof. In some embodiments, the antioxidant is sodiummetabisulfite, sodium thiosulfate, acetyl cysteine, BHA, BHT, vitamin E,ascorbic acid, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid(TROLOX®), or a combination thereof. In specific embodiments,compositions described herein comprise EDTA in an amount of about 0.03wt %. In some embodiments, a composition or formulation described hereincomprises a tonicity adjusting agent (e.g., sodium chloride) in anamount of about 0.13 wt % (or is prepared using such an amount oftonicity adjusting agent). In certain embodiments, preservatives arepresent in an amount of about 0.003 wt %.

In some embodiments, a composition or formulation disclosed herein doesnot contain a buffer system. In further embodiments, a composition orformulation disclosed herein does not contain an antioxidant. In someembodiments, a composition disclosed herein contains neither a buffersystem nor an antioxidant. In some embodiments, a composition orformulation disclosed herein does not contain a antimicrobialpreservative.

Also disclosed herein is a method of treating high IOP includingglaucoma, ocular hypertension, or a combination thereof comprisingtopically administering the formulations disclosed herein to the eye ofa patient in need thereof. Dosing and the frequency of administrationdepend on the severity of the condition and individual characteristicsof the patient. A typical frequency of administration for the treatmentof high IOP including glaucoma, ocular hypertension, or a combinationthereof is daily, e.g., once daily, twice daily, thrice daily, etc. Theformulations disclosed herein are mixed with suitable carriers,excipients, diluents, or a combination thereof to generate a preparationfor topical administration to the eye. Examples of suitable preparationsinclude eye drops, ophthalmic gels and ointments, and collyria.

In specific embodiments, compositions or formulations set forth hereinare prepared by combining the components set forth in Table 3. In morespecific embodiments, the composition or formulation is formulated in anaqueous medium (e.g., water), e.g., as a solution. In still morespecific embodiments, the composition or formulation as an osmolarity ofabout 280 mOsm/L to about 320 mOsm/L.

TABLE 3 Ingredient Weight Percentage Dorzolamide•hydrochloride  2.23%Latanoprost 0.005% HP-β-Cyclodextrin 2.0%-10% NaCl 0.135% Polyhexanide(PHMB) 0.003% Disodium EDTA 0.036% NaOH (4N) q.b. pH = 6.10 Sodiumhyaluronate (HTL)  0.05%

EXAMPLES Example 1 A Representative Ophthalmic Latanoprost-DorzolamideFormulation at pH 6.1

In certain instances, an ophthalmic collyrium is prepared by combiningthe agents set forth in Table 4:

TABLE 4 Ingredient Weight Percentage Dorzolamide•hydrochloride  2.23%Latanoprost 0.005% HP-β-Cyclodextrin 2.0%-10% NaCl 0.135% Polyhexanide(PHMB) 0.003% Disodium EDTA 0.036% NaOH (4N) q.b. pH = 6.10 Sodiumhyaluronate (HTL)  0.05% pH = 6.10 Osmolarity = 280-320 mOsm/L

Example 2 Stability Analysis of Ophthalmic Latanoprost-DorzolamideFormulations

The formulation of Example 1 is stored for six months at two differenttemperatures (25 and 40° C.), and the percentage of active ingredientsremaining in the formulation is assessed each month following theinitiation of storage. The results of the stability analysis for theformulation of Example 1 are summarized in Tables 5-6.

TABLE 5 Storage Latanoprost Dorzolamide Temper- Months RemainingRemaining ature of pH Osmolarity (%) (%) 25° C. 6.0-6.2 250-32090.0%-110% 90.0%-110% mOsm/Kg 1 6.10 305 98.5 101.1 2 6.10 307 100.2100.5 3 6.08 307 99.8 99.5 4 6.09 311 99.5 100.1 5 6.11 310 97.6 99.8 66.11 311 98.4 101.0

TABLE 6 Storage Latanoprost Dorzolamide Temper- Months RemainingRemaining ature of pH Osmolarity (%) (%) 40° C. 6.0-6.2 250-32090.0%-110% 90.0%-110% mOsm/Kg 1 6.10 99.8 100.1 2 6.11 101.2 99.9 3 6.1099.8 99.5 4 6.13 98.7 100.5 5 6.12 99.5 99.6 6 6.13 98.5 98.9

A formulation similar to the exemplified product in Example 1, but witha pH equal to 6.8, is prepared for comparison in a stability analysis.The composition of the formulation is described in the Table 7.

TABLE 7 Ingredient Weight Percentage Dorzolamide•hydrochloride  2.23%Latanoprost 0.005% HP-β-Cyclodextrin  8.0% NaCl 0.135% Polyhexanide(PHMB) 0.003% Disodium EDTA 0.036% NaOH (4N) q.b. pH = 6.80 Sodiumhyaluronate (HTL)  0.05% pH = 6.80 Osmolarity = 310 mOsm/L

The formulation at pH=6.8 was stored for six months at two differenttemperatures (25 and 40° C.), and the percentage of active ingredientsremaining in the formulation was assessed at each month following theinitiation of storage. The results of the stability analysis aresummarized Tables 8 and 9.

TABLE 8 Storage Latanoprost Dorzolamide Temper- Months RemainingRemaining ature of pH Osmolarity (%) (%) 25° C. 6.7-6.9 250-32090.0%-110% 90.0%-110% mOsm/kg 1 6.80 313 101.3 101 2 6.77 306 102.5 99.13 6.75 309 104.1 100.4 4 6.85 310 102.9 98.5 5 6.82 306 102.6 94.3 66.83 302 99.8 92.9

TABLE 9 Storage Latanoprost Dorzolamide Temper- Months RemainingRemaining ature of pH Osmolarity (%) (%) 40° C. 5.7-6.9 250-32090.0%-110% 90.0%-110% mOsm/kg 1 6.75 313 102.1 98.8 2 6.80 307 101.396.0 3 6.82 311 105.3 92.7 4 6.87 307 100.1 90.9 5 6.95 305 102.6 93.6 66.89 303 97.4 89.5

As can be seen in the tables above, a formulation comprisinglatanoprost, dorzolamide, HP-β-cyclodextrin, and sodium hyaluronate witha pH of 6.1 is stable under long-term storage at room and elevatedtemperatures. Conversely, a similarly formulated composition with a pHof 6.8 yields significant decomposition of the active agents underidentical storage conditions. Thus, formulating latanoprost anddorzolamide as described herein results in an ophthalmic compositionthat achieves superior long-term stability of the active agents, and issuitable for coadministration of the drugs for the treatment of high IOPincluding glaucoma, ocular hypertension, or a combination thereof.

Example 3 Stability of Dorzolamide at 25° C. in a Formulation Accordingto Example 1 with HP-β-cyclodextrin at 8.0% and Varying pH Levels

Multiple formulations are prepared according to Example 1, with theconcentration of HP-β-cyclodextrin at 8.0%, and the pH varying between6.1 and 6.8. The formulations re stored at 25° C. for up to six months,and the percentage of dorzolamide remaining in the formulation ismeasured each month following initiation of storage. The results aresummarized in Tables 10-13.

As is seen in Tables 10-13, formulations having a pH above 6.20 exhibitdegradation in dorzolamide that is excessive or at the limit ofacceptability for the preservation of the dorzolamide-latanoprostcombination at ambient temperature. Formulations prepared with a pHbelow 6.20 achieve suitable stability of dorzolamide for long-termstorage and subsequent coadministration of the active agents.

TABLE 10 Titration % pH Dorzolamide Dorzolamide Months 6.0-6.2 90.0-110%25° C. 1 6.10 101 pH = 6.1 2 6.10 99.8 3 6.08 100 4 6.09 100 5 6.11 98.86 6.11 99.9

TABLE 11 Titration % pH Dorzolamide Dorzolamide Months 6.1-6.3 90.0-110%25° C. 1 6.20 101 pH = 6.2 2 6.21 99.8 3 6.18 99.5 4 6.21 97.5 5 6.2397.0 6 6.23 97.8

TABLE 12 Titration % pH dorzolamide Dorzolamide Months 6.4-6.6 90.0-110%25° C. 1 6.52 102 pH = 6.5 2 6.52 99.8 3 6.60 97.5 4 6.55 95.5 5 6.6093.8

TABLE 13 Titration % pH dorzolamide Dorzolamide Months 6.7-6.9 90.0-110%25° C. 1 6.80 101 pH = 6.8 2 6.77 99.1 3 6.75 100 4 6.85 98.5 5 6.8294.3

Example 4 Stability of Dorzolamide Formulations According to Example 1at 40° C. with HP-β-cyclodextrin at 8.0% and Varying pH

The stability of formulations according to Example 1 withHP-β-cyclodextrin at 8.0% and with varying pH levels are also assessedunder elevated temperatures (40° C.), as set forth in Table 14. Theremaining percentage of dorzolamide in the formulations was measured at10, 15, and 30 days following initiation of storage. As with thestability studies at ambient temperature, a pH above 6.2 resulted insignificant decomposition of dorzolamide under the acceleratedconditions. Formulations prepared according to the disclosure herein,however, maintained suitable concentrations of dorzolamide even underthe harsher conditions.

TABLE 14 10 days 15 days 30 days Titration % dorzolamide pH = 6.10 (a)101% 99.5%  101% pH(a) 6.10 6.12    6.12 Osmolarity (a) 289 285 290Titration % dorzolamide pH = 6.20 (b) 100% 98.1% 97.2% pH(b) 6.21 6.23   6.23 Osmolarity (b) 304 307 309 Titration % dorzolamide pH = 6.50 (c)99% 95.6% 89.6% pH(c) 6.46 6.49    6.50 Osmolarity (c) 283 287 283Titration % dorzolamide pH = 6.80 (d) 100% 92.6% 86.6% pH(d) 6.78 6.70   6.70 Osmolarity (d) 311 305 309

Example 5 Acute Ocular Tolerability of an OphthalmicLatanoprost-Dorzolamide Formulation at pH=6.1 Compared to an EquivalentFormulation at pH=6.8 and a Placebo at pH=6.8

Two drops of each of the formulations described above are instilled inthe right eye of each animal 3 times on the same day at an interval of 2hours. Every group of rabbits consisted of 8 animals (4 males and 4females).

The condition of the ocular tissue is observed according to the DraizeTest. The examination is conducted after the third instillation on theday of the treatment and also 24, 48 and 72 hours after the firstinstillation, assigning arbitrary scores to the various aspects of theconjunctiva of the iris and cornea. No significant reddening of theconjunctiva is observed for the entire period of the test, both in theeyes treated with the pH=6.1 formulation and in those treated withpH=6.8 formulation, as well as with the placebo. No edema or opacity isobserved at the corneal level. In addition, no involvement of the irisis observed. The presence of drainage material stayed at normal level.Mild de-epithelization is observed in three eyes treated with the pH=6.1formulation and in two eyes treated with the pH=6.8 formulation.

The results obtained show that the ophthalmic solution at pH=6.1 is welltolerated after repeated instillations (three in 6 hours), and there areno difference versus the pH=6.8 formulation and its placebo, also atpH=6.8.

Example 6 Test of an Ophthalmic Latanoprost-Dorzolamide Formulation inan Animal Model of Glaucoma

Elevated intraocular pressure is induced in rats by cauterization ofthree of the four episcleral veins. Following stabilization ofintraocular pressure, rats with sustained elevated intraocular pressurelevels (typically 1.5-1.8 times normal) are selected for the test. Ratswith high intraocular pressure are daily administered either anophthalmic latanoprost-dorzolamide formulation disclosed herein or thecarrier for the formulation alone as a control. In order to assess theefficacy of administering a stable, ophthalmic latanoprost-dorzolamideformulation disclosed herein for the treatment of ocular hypertensionand glaucoma, the absolute and relative (percentage from baseline)reduction of intraocular pressure is measured for both groups over athree-month period, and the average values for the test group at varioustime points are compared to the average values for the control group atthe corresponding time points. At the end of the test period, the ratsare sacrificed and the extent of retinal ganglion cell death ismeasured. The extent of ganglion cell death is compared in the test andcontrol groups to assess the efficacy of the formulations disclosedherein in inhibiting the progression or onset of glaucoma induced byocular hypertension.

Example 7 Clinical Trial of an Ophthalmic Latanoprost-DorzolamideFormulation for the Treatment of Ocular Hypertension and Primary OpenAngle Glaucoma

Patients selected for inclusion in the trial have an intraocularpressure greater than 20 mmHg resulting from ocular hypertension orprimary open angle glaucoma. Patients included in the trial are alsonaive (have never been treated for ocular hypertension) and requiretreatment initiation. Primary outcomes of the study are the absolutevalue and relative magnitude (percentage from baseline) of intraocularpressure reduction after three months of treatment. The reduction ofintraocular pressure is also assessed at one and two months followingtreatment initiation.

Patients in the test group are topically administered alatanoprost-dorzolamide formulation according to Example 1. Patients inthe control group are topically administered either an ophthalmiclatanoprost formulation (0.005% latanoprost, XALATAN®) or dorzolamideformulation (2% dorzolamide, TRUSOPT®) daily for three months followingrecommended dosing procedures. Intraocular pressure is measured bystandard tonometry tests (applanation, electronic indentation, ornoncontact tonometry).

The absolute and relative reduction of intraocular pressure followingadministration of a combination latanoprost-dorzolamide formulationdisclosed herein is compared to the absolute and relative reduction fromadministration of each of the individual therapies alone. The averageabsolute and relative reduction in intraocular pressure followingadministration of a combination formulation is also compared to thecombination of the average results from the single agent therapies toassess the synergy of coadministering the active agents in a single,stable ophthalmic formulation.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A stable ophthalmic pharmaceutical compositionfor the treatment of glaucoma, ocular hypertension, or a combinationthereof, the stable ophthalmic pharmaceutical composition comprising:(a) a therapeutically-effective amount of dorzolamide, or apharmaceutically acceptable salt thereof, (b) atherapeutically-effective amount of latanoprost, and (c) a cyclodextrin,wherein the composition has a pH between about 6.0 and about 6.2, andwherein the composition is stable with respect to degradation of thedorzolamide and latanoprost for at least 4 months.
 2. The stableophthalmic pharmaceutical composition according to claim 1, furthercomprising a mucoadhesive, a preservative, a pH-adjusting agent, atonicity-adjusting agent, a buffering agent, an antioxidant, or acombination thereof.
 3. The stable ophthalmic pharmaceutical compositionaccording to claim 2, further comprising a therapeutically effectiveamount of an additional anti-glaucoma agent.
 4. The stable ophthalmicpharmaceutical composition according to claim 3, wherein the additionalanti-glaucoma agent is a beta blocker.
 5. The stable ophthalmicpharmaceutical composition according to claim 4, wherein the betablocker is timolol.
 6. The stable ophthalmic pharmaceutical compositionaccording to claim 1, wherein the pharmaceutically acceptable salt ofdorzolamide is dorzolamide hydrochloride.
 7. The stable ophthalmicpharmaceutical composition according to claim 1, wherein thecyclodextrin is hydroxypropyl-β-cyclodextrin.
 8. The stable ophthalmicpharmaceutical composition according to claim 2, wherein themucoadhesive is hyaluronic acid or a pharmaceutically acceptable saltthereof, polyvinyl alcohol, polyvinyl-pyrrolidone,hydroxypropyl-methylcellulose, carboxymethyl-cellulose, hydroxyethylcellulose, a poloxamer, alginic acid, chitosan, xanthan gum,carrageenan, acrylic acid, acrylic acid derivatives, or a combinationthereof.
 9. The stable ophthalmic pharmaceutical composition accordingto claim 2, wherein the preservative is benzalkonium chloride,chlorobutanol, phenylmercuric acetate, phenylmercuric nitrate,polyhexinide, cetrimide, cetylpyridinium chloride, EDTA, or acombination thereof.
 10. The stable ophthalmic pharmaceuticalcomposition of claim 2, wherein the pH-adjusting agent is hydrochloricacid, boric acid, acetic acid, sodium hydroxide, potassium hydroxide, ora combination thereof.
 11. The stable ophthalmic pharmaceuticalcomposition of claim 2, wherein the tonicity-adjusting agent is sodiumchloride, potassium chloride, mannitol, glycerol, sorbitol, xylitol, ora combination thereof.
 12. The stable ophthalmic pharmaceuticalcomposition of claim 2, wherein the buffering agent is an acetatebuffer, a citrate buffer, a phosphate buffer, a borate buffer, or acombination thereof.
 13. The stable ophthalmic pharmaceuticalcomposition of claim 2, wherein the antioxidant is sodium metabisulfite,sodium thiosulfate, acetyl cysteine, BHA, BHT, vitamin E, ascorbic acid,6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, or a combinationthereof.
 14. The stable ophthalmic pharmaceutical composition accordingto claim 1, wherein the composition comprises the following componentsin the following weight percentages: dorzolamide hydrochloride 1-3%latanoprost 0.003-0.01%  HP-β-cyclodextrin   2-10%.


15. A stable ophthalmic pharmaceutical composition comprising: (a) atherapeutically-effective amount of dorzolamide, or a pharmaceuticallyacceptable salt thereof, (b) a therapeutically-effective amount oflantanoprost, and (c) a cyclodextrin, wherein the composition has a pHbetween about 6.0 and about 6.2, and wherein the composition is stablewith respect to degradation of the dorzolamide and latanoprost for atleast 4 months.
 16. The stable ophthalmic pharmaceutical compositionaccording to claim 15, wherein after 6 months of storage at 25° C. or at40° C., the composition comprises at least 97% of the initial amount ofdorzolamide, and at least 98% of the initial amount of latanoprost. 17.A method of treating glaucoma, ocular hypertension, or a combinationthereof, comprising topically administering a stable ophthalmicpharmaceutical composition according to claim 1 to the eye of a patientin need thereof.